X-133753688-C-T

Variant names:

• chrX-133753688-C-T
• rs141100113
• NM_004484.4:c.826G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_004484.4(GPC3):​c.826G>A​(p.Gly276Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00016 in 1,209,642 control chromosomes in the GnomAD database, including 1 homozygotes. There are 41 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G276C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00073 (0 hom., 20 hem., cov: 22)
  • Exomes 𝑓: 0.00010 (1 hom. 21 hem.)
• Consequence: GPC3 NM_004484.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6 O:1
• Conservation: PhyloP100: 3.10
• Publications: 12 publications found

Genes affected

GPC3 (HGNC:4451): (glypican 3) Cell surface heparan sulfate proteoglycans are composed of a membrane-associated protein core substituted with a variable number of heparan sulfate chains. Members of the glypican-related integral membrane proteoglycan family (GRIPS) contain a core protein anchored to the cytoplasmic membrane via a glycosyl phosphatidylinositol linkage. These proteins may play a role in the control of cell division and growth regulation. The protein encoded by this gene can bind to and inhibit the dipeptidyl peptidase activity of CD26, and it can induce apoptosis in certain cell types. Deletion mutations in this gene are associated with Simpson-Golabi-Behmel syndrome, also known as Simpson dysmorphia syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]

GPC3 Gene-Disease associations (from GenCC):

• Simpson-Golabi-Behmel syndrome

  Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Simpson-Golabi-Behmel syndrome type 1

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.036491454).
• BP6: Variant X-133753688-C-T is Benign according to our data. Variant chrX-133753688-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 95100.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000731 (82/112129) while in subpopulation AFR AF = 0.00239 (74/30901). AF 95% confidence interval is 0.00196. There are 0 homozygotes in GnomAd4. There are 20 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 20 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004484.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPC3	NM_004484.4	MANE Select	c.826G>A	p.Gly276Ser	missense	Exon 3 of 8	NP_004475.1	I6QTG3
	GPC3	NM_001164617.2		c.826G>A	p.Gly276Ser	missense	Exon 3 of 9	NP_001158089.1	P51654-3
	GPC3	NM_001164618.2		c.778G>A	p.Gly260Ser	missense	Exon 3 of 8	NP_001158090.1	B4DTD8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPC3	ENST00000370818.8	TSL:1 MANE Select	c.826G>A	p.Gly276Ser	missense	Exon 3 of 8	ENSP00000359854.3	P51654-1
	GPC3	ENST00000394299.7	TSL:1	c.826G>A	p.Gly276Ser	missense	Exon 3 of 9	ENSP00000377836.2	P51654-3
	GPC3	ENST00000631057.2	TSL:1	c.664G>A	p.Gly222Ser	missense	Exon 2 of 7	ENSP00000486325.1	P51654-2

Frequencies

GnomAD3 genomes AF: 0.000732 AC: 82 AN: 112075 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00240

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000474

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000373

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00132

GnomAD2 exomes AF: 0.000246 AC: 45 AN: 183233 AF XY: 0.000162

Gnomad AFR exome AF: 0.00243

Gnomad AMR exome AF: 0.000328

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000722

Gnomad FIN exome AF: 0.0000625

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000443

GnomAD4 exome AF: 0.000102 AC: 112 AN: 1097513 Hom.: 1 Cov.: 33 AF XY: 0.0000579 AC XY: 21 AN XY: 362883

African (AFR) AF: 0.00307 AC: 81 AN: 26384

American (AMR) AF: 0.000398 AC: 14 AN: 35205

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19379

East Asian (EAS) AF: 0.0000993 AC: 3 AN: 30204

South Asian (SAS) AF: 0.00 AC: 0 AN: 54127

European-Finnish (FIN) AF: 0.0000247 AC: 1 AN: 40530

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.00000238 AC: 2 AN: 841479

Other (OTH) AF: 0.000239 AC: 11 AN: 46069

GnomAD4 genome AF: 0.000731 AC: 82 AN: 112129 Hom.: 0 Cov.: 22 AF XY: 0.000583 AC XY: 20 AN XY: 34313

African (AFR) AF: 0.00239 AC: 74 AN: 30901

American (AMR) AF: 0.000473 AC: 5 AN: 10564

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2651

East Asian (EAS) AF: 0.00 AC: 0 AN: 3566

South Asian (SAS) AF: 0.000374 AC: 1 AN: 2677

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6110

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53221

Other (OTH) AF: 0.00130 AC: 2 AN: 1534

Alfa AF: 0.000271 Hom.: 15

Bravo AF: 0.00105

ESP6500AA AF: 0.00209 AC: 8

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000239 AC: 29

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Wilms tumor 1 (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.0
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.49	D
MetaRNN	Benign	0.036	T
MetaSVM	Benign	-0.43	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		3.1
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.020	D
Polyphen		1.0	D
Vest4		0.17
MVP		0.84
MPC		0.60
ClinPred		0.11	T
GERP RS		6.0
PromoterAI		-0.0039	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.69
gMVP		0.71
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs141100113; hg19: chrX-132887715; COSMIC: COSV63664668;